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CARDIOVASCULAR

Novel Peroxisome Proliferator-Activated Receptor Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist

Department of Atherosclerosis (R.M., B.M., D.M., H.M., R.Z., D.S., D.G., M.B., R.S.), Leads Evaluation Group (K.T.L., K.M.O., L.Z.), Bioanalytical Discovery Analytical Sciences (M.F.), and Metabolic Disease Chemistry (J.L., Y.S., L.J.K., P.T.C., J.T.), Bristol-Myers Squibb Company, Research and Development, Pennington, New Jersey

The first generation peroxisome proliferator-activated receptor (PPAR) agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPAR agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPAR-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPAR than human PPAR; therefore, they were tested in PPAR-humanized mice that do not express murine PPAR but express human PPAR selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPAR in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPAR agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.

Address correspondence to: Dr. Ranjan Mukherjee, Bristol-Myers Squibb Company, 311 Pennington Rocky Hill Road, Pennington, NJ 08534. E-mail: ranjan.mukherjee{at}bms.com.